Hereditary tyrosinaemia (type I) is an inborn error of metabolism. Patients suffer from multi-organ symptoms and may develop severe liver failure at a very early age, or more progressively liver disease which leads to nodular cirrhosis and the development of primary hepatic carcinoma. Damage to the kidneys and blood forming organs may also occur. Death usually occurs before the age of 20, but single patients have reached higher ages. Some patients develop symptoms characteristic of acute porphyria with episodes of acute abdominal pain and a generalised paresis. The excretion of 5-aminolevulinic acid (a precursor of porphyrins) is elevated. A porphyric episode may be the cause of death. There is no impairment of intelligence or central nervous system function. The incidence in Sweden is about 1 in 100,000 births. However, in certain regions of Canada the incidence is higher, for example, in the Lac-St Jean area of Quebec, it is about 1 in 1800 births.
The disease was named following the initial finding of high tyrosine concentrations in blood and the excretion of `phenolic acids` in urine. Originally it was supposed that the primary enzyme defect was a deficiency of HPPD, which enzyme is responsible for catalysing the conversion of 4-hydroxyphenylpyruvate (the primary product of the action of tyrosine aminotransferase) to homogentisate. However, it was noted that those patients with a considerable residual activity of this enzyme had a more severe form of the disease.
Patients with hereditary tyrosinaemia (type I) excrete succinylacetoacetate and succinylacetone as well as 5-aminolevulinic acid. The plasma concentration of .alpha.-fetoprotein is often high and a dramatic increase in this protein may indicate the development of liver cancer. Succinylacetoacetate may be formed from fumaryl-acetoacetate, which is normally hydrolysed by the enzyme fumarylacetoacetase and also from maleylacetoacetate (the product of the action of homogentisate 1,2-dioxygenase on homogentisate). Based on the excretion of succinylacetoacetoacetate and succinylacetone by patients with hereditary tyrosinaemia (type I), Lindstedt and co-workers (Proc. Natl. Acad. Sci., 1977, 74, 4641-4645) have concluded that the primary defect in the disease is a deficiency in the enzyme fumarylacetoacetase.
The biochemical inter-relationship of the products of tyrosine metabolism is shown for information in FIG. 1. Succinylacetone is a powerful inhibitor of porphobilinogen synthase which catalyses the formation of porphobilinogen from 5-aminolevulinic acid in the haem biosynthetic pathway. This provides an explanation for the elevated excretion of 5-aminolevulinic acid and the porphyric symptoms.
The principal treatment of hereditary tyrosinaemia (type I) is based on restricting tyrosine dietary intake. This is not normally effective in preventing the fatal outcome of the disease. Liver transplantation may be performed in some patients producing some amelioration of the disease. However, since tyrosine degradation occurs in both the liver and the kidneys, liver transplantation may not prevent the development of severe kidney damage frequently associated with tyrosinaemia (type I). Accordingly, there is a continuing need for an effective means of treating diseases and related conditions such as tyrosinaemia (type I).
It has now been discovered (and this is the basis for the invention) that the compound 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione is an inhibitor of the catalytic activity of the enzyme HPPD and may be useful in the treatment of diseases where the products of the action of HPPD are involved, for example in treating tyrosinaemia (type I).